HI-6 is a bis-pyridinium oxime antidote to certain organophosphate nerve agents, HI-6 has the chemical formula I:

Wherein R is a suitable counterion. Suitable counterions include chloride and methanesulphonate.
HI-6 with chloride as the counterion has the chemical name (1-(((4-(aminocarbonyl)pyridinio)methoxy)-methyl)-2-((hydroxyimino)methyl)pyridinium dichloride monohydrate (CAS 34433-31-3), and has been known for many years as a suitable antidote for organophosphate nerve agents. Known regimens for producing HI-6 dichloride (2Cl) have involved the use of bis(chloromethyl)ether as a quaternization reagent for the pyridinium moieties pyridine-2-aldoxime (P2A) and isonicotinamide (INA). The reaction scheme proceeds as follows:

This conventional method for manufacturing HI-6 has the disadvantage that the reagent bis(chloromethyl)ether is itself highly toxic. A medicament used as antidote against a nerve toxin will preferably be free from highly toxic materials, even incidental amounts thereof left over from a starting reagent. Even if the end product can be guaranteed free of the carcinogenic bis(chloromethyl)ether, it is highly undesirable for this compound even to be used in the manufacturing process because of the potential health hazard to personnel involved in its manufacture and use.
Another recognized HI-6 antidote is HI-6 in which the counterion is methanesulfonate, HI-6 dimethanesulfonate (DMS). Some studies (eg Thiermann et al., International Journal of Pharmaceutics, 137 (1996) 167-176) have reported advantageous properties of HI-6 DMS compared to HI-6 2Cl. HI-6 DMS can be obtained from HI-6 2Cl by an ion exchange chromatography process:

However, this manufacturing route for HI-6 DMS still has the disadvantage that the highly toxic bis(chloromethyl)ether is used in the synthesis, with the attendant risk that traces of this material may be present as a contaminant in any end product medicament comprising HI-6 DMS, or that the reagent used in the manufacturing process may affect adversely the health of any person involved in its manufacture, storage, transport or use.
There have been proposed alternative routes to HI-6 DMS, directly from the starting oxime, and using bis(methylsulfonoxymethyl)ether (BSME) as an alternative quaternization agent. Yang et al. have proposed, in Bull. Korean Chem. Soc. 2003 Vol. 24, No. 9, 1368-1370, such a route but with very poor yields of the product material. Similar problems attend the disclosure of U.S. Pat. No. 5,130,438 of Hsiao et al. In both cases HI-6 DMS yields of 11% (with respect to P2A) are quoted after multiple fractional recrystallization. The scheme for these prior art syntheses may be summarized as:

Wherein the pyridine-2-aldoxime and isonicotinamide dimers are unwanted side products, present in the product mixture in unsatisfactorily high proportions. These unwanted side products have similar solubility properties to HI-6 DMS and are difficult to remove from the product. Thus it is difficult to obtain HI-6 DMS of satisfactory purity using such synthetic routes.